In the past decade, a large number of antineoplastic terpenoids have been isolated from natural sources. Since the purified antitumor agents are frequently available in only milligram quantities, new sources of the active compounds and their derivatives are clearly needed for thorough testing. The proposed research is aimed at the development of total synthesis of some of the most active of these compounds with particular emphasis on the efficiency of the routes to be developed. The research to be undertaken is an expansion of our previous program on the synthesis of terpenoid antitumor agents. We have recently developed an extremely efficient and highly stereoselective synthetic approach to macrocyclic natural products. Since these compounds, the germacranes and cembranes, are otherwise extremely difficult to approach synthetically, and since they include a large number of potent cytotoxins and antitumor agents, we plan to extend our studies further into this area. In particular we are proposing synthetic approaches to the highly oxygenated germacranolides and cembrenolides. We are also in the final stages of a total synthesis of trichodermol. Since this compound forms the nucleus of the verrucarin, baccharin and roridin macrolactones, we are proposing an extension of our work to lead to these potentially importnat antitumor agents. It should be pointed out that a number of these compounds are among the most cytostatic agents known showing 50% tumor inhibition in mice at concentrations less than or equal to 10 to the minus 3rd power micrograms/ml.